Dysregulation of the host immune system that weakens cardiac function greatly increases the odds of sepsis-induced death in critically ill patients. Despite decades of intensive study, basic mechanisms remain elusive. In particular, autopsy results indicate that most patients with sepsis had unresolved infectious foci, suggesting that impaired macrophage function fails to eradicate the invading pathogens. Therefore, any strategies that boost macrophage function would be expected to improve overall patient survival. We recently made the novel findings that the levels of secreted and transmembrane 1 (Sectm1), a protein normally highly expressed in immune cells of myeloid lineage and epithelial cells, was significantly lower in the blood of septic patients than healthy donors. Consistently, our latest data also showed that the expression levels of Sectm1a, a mouse homolog of human Sectm1, were greatly reduced in peripheral blood monocytes and peritoneal macrophages collected from septic mice, compared to control mice. Accordingly, Sectm1a-knockout (KO) mice exhibited: 1) a higher bacterial load in the blood and peritoneal lavage fluid, 2) an increased systemic inflammatory response, and 3) a deteriorated cardiac function as well as a lower survival rate, compared to wild-type (WT) mice under sepsis conditions. Mechanistically, Sectm1a-KO macrophages showed the impaired capacity of phagocytosis and bacterial killing. By contrast, forced expression of Sectm1a in macrophages augmented phagocytic capacity and bactericidal activity. Hence, it will be important to test whether macrophage-specific overexpression of Sectm1a can protect against sepsis through enhancing bacterial clearance. Our pilot data have also revealed that macrophage Sectm1a can elicit autocrine action by binding strongly to the membrane receptor of TNFRSF18 (TNF receptor superfamily membrane 18, also known as GITR or CD357, hereafter GITR). Follow-up experiments showed that treatment of macrophages with recombinant Sectm1a protein activated GITR signaling, which in turn enhanced phagocytic capacity. Thus, it will be important to test if injection of recombinant Sectm1a protein into septic mice not only promotes bacterial clearance, but also reduces the systemic inflammatory response, and improves myocardial function as well as animal survival. These translational ideas will be tested by pursuing three specific aims: 1) Define the exact role of Sectm1a in macrophages during polymicrobial sepsis, using a macrophage-specific Sectm1a-overexpressing mouse model; 2) Identify the mechanism by which Sectm1a-elicited anti- sepsis is dependent on GITR, using a GITR-knockout mouse model; and 3) Investigate the therapeutic potential using recombinant Sectm1a protein to treat sepsis. The proposed studies are expected to identify Sectm1a as a potent and novel regulator of host immunity and a major protector against sepsis. If verified, the findings from this proposal should provide new therapeutic options for boosting macrophage function in the clearance of bacteria during sepsis and hopefully, to minimize sepsis-induced death.